Anti-IGF-I receptor antibody

Abstract

Antibodies, humanized antibodies, resurfaced antibodies, antibody fragments, derivatized antibodies, and conjugates of these molecules with cytotoxic agents, which specifically bind to and inhibit insulin-like growth factor-I receptor, antagonize the effects of IGF-I and are substantially devoid of agonist activity toward the insulin-like growth factor-I receptor. These molecules can be conjugated to cytotoxic agents for use in the treatment of tumors that express elevated levels of IGF-I receptor, such as breast cancer, colon cancer, lung cancer, ovarian carcinoma, synovial sarcoma and pancreatic cancer. These molecules can also be labeled for in vitro and in vivo diagnostic uses, such as in the diagnosis and imaging of tumors that express elevated levels of IGF-I receptor.

1. A composition comprising an antibody or fragment thereof, wherein said antibody or said fragment comprises a heavy chain variable region and a light chain variable region, wherein said heavy chain variable region comprises the amino acid sequence of SEQ ID NO:7, and wherein said light chain variable region comprises a CDR1having the amino acid sequence of SEQ ID NO: 4, a CDR2 having the amino acid sequence of SEQ ID NO:5 and a CDR3 having the amino acid sequence of SEQ ID NO:6; and a therapeutic agent; wherein said antibody or said fragment specifically binds IGF-IR. 
     
     
       2. A composition comprising an antibody or fragment thereof, wherein said antibody or said fragment comprises a heavy chain variable region and a light chain variable region, wherein said light chain variable region comprises the amino acid sequence of SEQ ID NO:8, and wherein said heavy chain variable region comprises a CDR1 having the amino acid sequence of SEQ ID NO: 1, a CDR2 having the amino acid sequence of either SEQ ID NO:2 or SEQ ID NO:54 and a CDR3 having the amino acid sequence of SEQ ID NO:3; and a therapeutic agent; wherein said antibody or said fragment specifically binds IGR-IR. 
     
     
       3. A composition comprising an antibody or fragment thereof, wherein said antibody or said fragment comprises a heavy chain variable region and a light chain variable region, and wherein said antibody or said fragment specifically binds IGR-IR, wherein said light chain region comprises the amino acid sequence selected from the group consisting of:
 SEQ ID NO:9; 
 SEQ ID NO:10; 
 SEQ ID NO:11; and 
 SEQ ID NO:12; and wherein said heavy chain variable region a CDR1 having the amino acid sequence of SEQ ID NO: 1, a CDR2 having the amino acid sequence of either SEQ ID NO:2 or SEQ ID NO:54 and a CDR3 having the amino acid sequence of SEQ ID NO:3; and 
 wherein said composition further comprises a therapeutic agent. 
 
     
     
       4. A composition comprising an antibody or fragment thereof, wherein said antibody or said fragment specifically binds IGF-IR, wherein said antibody comprises a heavy chain variable region and a light chain variable region, wherein said heavy chain variable region comprises the amino acid sequence of SEQ ID NO:13, and wherein said light chain variable region comprises a CDR1 having the amino acid sequence of SEQ ID NO: 4, a CDR2 having the amino acid sequence of SEQ ID NO:5 and a CDR3 having the amino acid sequence of SEQ ID NO:6; and a therapeutic agent. 
     
     
       5. A composition comprising an isolated antibody or fragment thereof, wherein said antibody or said fragment comprises at least one heavy chain variable region and at least one light chain variable region, wherein said heavy chain variable region comprises a CDR1 having the amino acid sequence of SEQ ID NO: 1, a CDR2 having the amino acid sequence of either SEQ ID NO:2 or SEQ ID NO:54 and a CDR3 having the amino acid sequence of SEQ ID NO:3, and wherein said light chain variable region comprises CDR1 having the amino acid sequence of SEQ ID NO: 4, a CDR2 having the amino acid sequence of SEQ ID NO:5 and a CDR3 having the amino acid sequence of SEQ ID NO:6, and wherein said antibody or said fragment specifically binds to IGF-IR; and
 a therapeutic agent. 
 
     
     
       6. The composition of any one of  claim 5 ,  1  or  2 - 4 , wherein said therapeutic agent is selected from the group consisting of docetaxel, paclitaxel, doxorubicin, epirubicin, cyclophosphamide, trastuzumab, capecitabine, tamoxifen, toremifene, letrozole, anastrozole, fulvestrant, exemestane, goserelin, oxaliplatin, carboplatin, cisplatin, dexamethasone, antide, bevacizumab, 5-fluorouracil, leucovorin, levamisole, irinotecan, etoposide, topotecan, gemcitabine, vinorelbine, estramustine, mitoxantrone, abarelix, zoledronate, streptozocin, rituximab, idarubicin, busulfan, chlorambucil, fludarabine, imatinib, cytarabine, ibritumomab, tositumomab, interferon alpha-2b, melphalam, bortezomib, altretamine, asparaginase, gefitinib, erlonitib, anti-EGF receptor antibody, interferon alpha-2a, vincristine, pamidronate, thalidomide, carmustine, prednisone, erythropoietin, bisphosphonate and an epothilone. 
     
     
       7. The composition of any one of  claim 5 ,  1  or  2 - 4 , wherein said therapeutic agent is selected from the group consisting of carboplatin, oxaliplatin, cisplatin, paclitaxel, docetaxel, gemcitabine, and camptothecin. 
     
     
       8. The composition of  claim 5 , wherein said therapeutic agent is selected from the group consisting of bortezomib, melphalan, thalidomide, doxorubicin, cyclophosphamide, interferon alpha-2b, interferon alpha-2a, vincristine, pamidronate, carmustine, zoledronate, and dexamethasone. 
     
     
       9. The composition of any one of  claim 5 ,  1  or  2 - 4 , wherein said therapeutic agent is selected from the group consisting of bortezomib, melphalan, doxorubicin, cyclophosphamide, interferon alpha-2b, interferon alpha-2a, vincristine, pamidronate, zoledronate, and dexamethasone. 
     
     
       10. The composition of  claim 5 , wherein said antibody or said fragment is selected from the group consisting of:
 (i) a resurfaced antibody or epitope binding fragment thereof; 
 (ii) a humanized antibody or epitope binding fragment thereof; and 
 (iii) an antibody produced by mouse hybridoma EM164 (ATCC accession number PTA 4457) or epitope binding fragment thereof. 
 
     
     
       11. A composition comprising an antibody or antibody fragment, wherein said antibody or said fragment specifically binds IGF-IR, and wherein said antibody comprises a heavy chain variable region and a light chain variable region, wherein said heavy chain variable region comprises a CDR1 having the amino acid sequence of SEQ ID NO: 1, a CDR2 having the amino acid sequence of either SEQ ID NO:2 or SEQ ID NO:54 and a CDR3 having the amino acid sequence of SEQ ID NO:3, and wherein said light chain variable region comprises CDR1 having the amino acid sequence of SEQ ID NO: 4, a CDR2 having the amino acid sequence of SEQ ID NO:5 and a CDR3 having the amino acid sequence of SEQ ID NO:6; and wherein said light chain variable region comprises the amino acid sequence of SEQ ID NO:8; and
 a therapeutic agent. 
 
     
     
       12. A composition comprising an antibody or antibody fragment, wherein said antibody or said fragment comprises at least one heavy chain variable region and at least one light chain variable region, wherein said heavy chain variable region comprises a CDR1 having the amino acid sequence of SEQ ID NO: 1, a CDR2 having the amino acid sequence of either SEQ ID NO:2 or SEQ ID NO:54 and a CDR3 having the amino acid sequence of SEQ ID NO:3, and wherein said light chain variable region comprises CDR1 having the amino acid sequence of SEQ ID NO: 4, a CDR2 having the amino acid sequence of SEQ ID NO:5 and a CDR3 having the amino acid sequence of SEQ ID NO:6, respectively, and wherein said heavy chain variable region comprises SEQ ID NO:7; and wherein said antibody or said fragment specifically binds IGF-IR; and
 a therapeutic agent. 
 
     
     
       13. A composition comprising the antibody or fragment thereof of  claim 5 , comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:13. 
     
     
       14. The composition of  claim 5  further comprising a pharmaceutically acceptable carrier. 
     
     
       15. A composition comprising a conjugate comprising the antibody or antibody fragment of  claim 5  linked to a cytotoxic agent. 
     
     
       16. The composition of  claim 15 , wherein said cytotoxic agent is selected from the group consisting of a maytansinoid, a small drug, a prodrug, a taxoid, CC-1065 and a CC-1065 analog. 
     
     
       17. A pharmaceutical composition comprising the conjugate of  claim 15  and a pharmaceutically acceptable carrier. 
     
     
       18. A composition comprising a diagnostic reagent comprising the composition of  claim 14 , wherein said antibody or antibody fragment is labeled with a detectable moiety. 
     
     
       19. The composition of  claim 18 , wherein said detectable moiety is selected from the group consisting of a radiolabel, a fluorophore, a chromophore, an imaging agent and a metal ion. 
     
     
       20. A composition comprising a murine antibody EM164 produced by ATCC deposit number PTA-4457 or a fragment thereof that specifically binds to an insulin-like growth factor-I receptor, wherein said antibody or fragment is an antagonist of said receptor and is devoid of agonist activity toward said receptor; and
 a therapeutic agent. 
 
     
     
       21. A composition comprising a humanized or resurfaced version of antibody EM164 produced by ATCC deposit number PTA-4457 or a fragment thereof that specifically binds to an insulin-like growth factor-I receptor, wherein said antibody or fragment is an antagonist of said receptor and is devoid of agonist activity toward said receptor; and
 a therapeutic agent. 
 
     
     
       22. A method for diagnosing a subject suspected of having a cancer comprising a cancer cell expressing IGF-IR, said method comprising:
 administering to said subject the composition of  claim 18 ; and 
 detecting the distribution of said reagent within said subject. 
 
     
     
       23. The method of diagnosis of  claim 22 , wherein said cancer is a cancer selected from the group consisting of breast cancer, colon cancer, ovarian carcinoma, osteosarcoma, cervical cancer, prostate cancer, lung cancer, synovial carcinoma and pancreatic cancer. 
     
     
       24. A method for inhibiting the growth of a cancer cell expressing IGF-IR comprising contacting said cell with the composition of  claim 5 . 
     
     
       25. A method for treating a patient having a cancer comprising a cancer cell expressing IGF-IR comprising administering to said patient an effective amount of the composition of  claim 5 . 
     
     
       26. The method of  claim 25  further comprising administering to said patient a second therapeutic agent. 
     
     
       27. The method of  claim 26 , wherein said therapeutic agent is a cytotoxic agent. 
     
     
       28. A method for treating a patient having a cancer comprising a cancer cell expressing IGF-IR comprising administering to said patient an effective amount of the conjugate of  claim 15 . 
     
     
       29. The method of treatment of  claim 25 , wherein said cancer is a cancer selected from the group consisting of breast cancer, colon cancer, ovarian carcinoma, osteosarcoma, cervical cancer, prostate cancer, lung cancer, synovial carcinoma and pancreatic cancer. 
     
     
       30. The method of  claim 24 , wherein said cancer is a cancer selected from the group consisting of breast cancer, colon cancer, ovarian carcinoma, osteosarcoma, cervical cancer, prostate cancer, lung cancer, synovial carcinoma, pancreatic cancer, melanoma, multiple myeloma, neuroblastoma, and rhabdomyosarcoma. 
     
     
       31. The method of  claim 26 , wherein said cell is contacted with said antibody or said fragment and said second therapeutic agent concurrently. 
     
     
       32. The method of  claim 26 , wherein said cell is contacted with said antibody or said fragment and said second therapeutic agent sequentially and in either order. 
     
     
       33. The method of  claim 26 , wherein said antibody or said fragment and said second therapeutic agent are administered concurrently. 
     
     
       34. The method of  claim 26 , wherein said antibody or said fragment and said second therapeutic agent are administered sequentially and in either order. 
     
     
       35. The method of  claim 24  or  26 , wherein said therapeutic agent is selected from the group consisting of docetaxel, paclitaxel, doxorubicin, epirubicin, cyclophosphamide, trastuzumab, capecitabine, tamoxifen, toremifene, letrozole, anastrozole, fulvestrant, exemestane, goserelin, oxaliplatin, carboplatin, cisplatin, dexamethasone, antide, bevacizumab, 5-fluorouracil, leucovorin, levamisole, irinotecan, etoposide, topotecan, gemcitabine, vinorelbine, estramustine, mitoxantrone, abarelix, zoledronate, streptozocin, rituximab, idarubicin, busulfan, chlorambucil, fludarabine, imatinib, cytarabine, ibritumomab, tositumomab, interferon alpha-2b, melphalam, bortezomib, altretamine, asparaginase, gefitinib, erlonitib, anti-EGF receptor antibody, interferon alpha-2a, vincristine, pamidronate, thalidomide, carmustine, prednisone, erythropoietin, bisphosphonate and an epothilone. 
     
     
       36. The method of  claim 24  or  26 , wherein said therapeutic agent is selected from the group consisting of carboplatin, oxaliplatin, cisplatin, paclitaxel, docetaxel, gemcitabine, and camptothecin. 
     
     
       37. The method of  claim 24  or  26 , wherein said therapeutic agent is selected from the group consisting of bortezomib, melphalan, doxorubicin, cyclophosphamide, interferon alpha-2b, interferon alpha-2a, vincristine, carmustine, zoledronate, and dexamethasone. 
     
     
       38. The method according to  claim 25 , wherein said effective amount of the composition of  claim 5  comprises about 1 mg/square meter to about 2000 mg/square meter of said antibody or fragment thereof, and about 10 mg/square meter to about 2000 mg/square meter of said therapeutic agent. 
     
     
       39. The method according to  claim 25 , wherein said effective amount of the composition of  claim 5  comprises about 10 mg/square meter to about 1000 mg/square meter of said antibody or fragment thereof, and about 50 mg/square meter to about 1000 mg/square meter of said therapeutic agent.